POS0719 RAPID EFFICACY OF ANIFROLUMAB IN MULTIPLE SUBTYPES OF RECALCITRANT CUTANEOUS LUPUS PARALLELS DISCRETE CHANGES IN TRANSCRIPTOMIC AND CELLULAR BIOMARKERS.
Authors: L. M. Carter, Z. Wigston, P. Laws, E. Vital
Journal: Annals of the Rheumatic Diseases (2022)

Background Cutaneous lupus eyrthematosus (CLE) is frequently refractory to immunosuppressive therapies including B-cell depletion, but this varies by morphology with the chronic discoid (DLE) subtype being particularly resistant. Local production and response to type-I interferon (IFN-I) is implicated in all subtypes of CLE. Therapeutic blockade of the IFN-I receptor with anifrolumab has direct effects on IFN-I signaling, and subsequent more widespread effects on other immune functions regulated by IFN-I[1]. Response to anifrolumab by lesion subtype have not been described, and it is unclear which effects of IFN-blockade are responsible for cutaneous response. We hypothesise that the efficacy of anifrolumab will differ dependent on the relative contribution of direct IFN-I effects vs. the downstream immunostimulatory effects of IFN-I on other immune functions. Objectives To evaluate the effect of anifrolumab on (i) rituximab-refractory CLE; (ii) on DLE; (iii) to compare clinical responses with IFN-specific biomarkers and transcriptomic evaluation of broader immune responses; (iv) to compare early and late immunophenotypic and clinical responses. Methods SLE patients with active recalcitrant CLE were treated with anifrolumab 300 mg IV every 4 weeks and evaluated using the cutaneous lupus erythematosus disease area and severity index (CLASI) and dermatology life quality index (DLQI). Fluorescence intensity of tetherin (CD317), a cell surface interferon biomarker, was evaluated on major cell subsets by multiparameter flow cytometry of peripheral blood mononuclear cells (PBMCs). Previously validated IFN-Scores-A and B [2], in addition to gene expression scores annotated to inflammation, myeloid lineage and plasmablasts modules [3], were measured in PBMCs using customised Taqman array at baseline, 1 month and 3 months into treatment. Results 8 patients (DLE n=5, chillblain / nodular vasculitis n=2, subacute CLE n=1) have enrolled to date. One month clinical and biomarker data are now available for 5. Median number of previously failed standard therapies is 6, including rituximab in 6/8 patients, belimumab in 3/8 and thalidomide in 4/8. Four patients required long-term oral prednisolone &gt;10 mg daily. Median baseline CLASI activity score was 16 and DLQI was 16/30. Rapid clinical responses were evident at 1 month in 4/5 patients, being greatest in magnitude in patients with SCLE and DLE compared with chillblain lesions. Median fall in CLASI activity score at 1 month was 6 points with a median percentage change from baseline of 31%. In all patients, a rapid and marked suppression of IFN-Score-A (mean difference 2.92, p&lt;0.01) and plasmablast tetherin (p=0.01), was evident by 1 month. Small and variable downward trends were observed in inflammation- and IFN-Score-B (p=0.06), myeloid (p=0.27) and plasmablast (p=0.15) -annotated gene expression scores. Major cell population numbers were proportionally unaltered in flow cytometry. Conclusion These preliminary results suggest that anifrolumab: (i) may be effective in rituximab-resistant CLE, (ii) is effective in DLE; (iii) rapidly suppresses IFN-I response, but with lesser effects on non-IFN immune biomarkers and (iv) early direct effects on IFN-I are associated with rapid clinical response. References [1]Morand et al., Engl J Med 2020; 382:211-221 [2]Banchereau et al., Cell 2016;165: 551-65 [3]El-Sherbiny et al., Sci. Rep. 2018; 8: 5793 Disclosure of Interests Lucy Marie Carter: None declared, Zoe Wigston: None declared, Philip Laws Speakers bureau: AbbVie, Actelion, BMS, Consultant of: Amgen, Celgene, Janssen, Leo, Lilly, Sanofi, Grant/research support from: UCB, Almirall, and Novartis, Edward Vital Consultant of: AstraZeneca, Genentech, Aurinia, Lilly, ILTOO and Modus Therapeutics., Grant/research support from: AstraZeneca and Sandoz